Acute Migraine Treatment in Adults

There are many options for acute migraine attack treatment, but none is ideal for all patients. This study aims to review current medical office‐based acute migraine therapy in adults and provides readers with an organized approach to this important facet of migraine treatment. A general literature review includes a review of several recent published guidelines. Acetaminophen, 4 nonsteroidal anti‐inflammatory drugs (NSAIDs) (ibuprofen, acetylsalicylic acid [ASA], naproxen sodium, and diclofenac potassium), and 7 triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan) have good evidence for efficacy and form the core of acute migraine treatment. NSAID–triptan combinations, dihydroergotamine, non‐opioid combination analgesics (acetaminophen, ASA, and caffeine), and several anti‐emetics (metoclopramide, domperidone, and prochlorperazine) are additional evidence‐based options. Opioid containing combination analgesics may be helpful in specific patients, but should not be used routinely. Clinical features to be considered when choosing an acute migraine medication include usual headache intensity, usual rapidity of pain intensity increase, nausea, vomiting, degree of disability, patient response to previously used medications, history of headache recurrence with previous attacks, and the presence of contraindications to specific acute medications. Available acute medications can be organized into 4 treatment strategies, including a strategy for attacks of mild to moderate severity (strategy one: acetaminophen and/or NSAIDs), a triptan strategy for patients with severe attacks and for attacks not responding to strategy one, a refractory attack strategy, and a strategy for patients with contraindications to vasoconstricting drugs. Acute treatment of migraine attacks during pregnancy, lactation, and for patients with chronic migraine is also discussed. In chronic migraine, it is particularly important that medication overuse is eliminated or avoided. Migraine treatment is complex, and treatment must be individualized and tailored to the patient's clinical features. Clinicians should make full use of available medications and formulations in an organized approach.     

Rescue therapy for acute migraine, part 3: opioids, NSAIDs, steroids, and post-discharge medications

Objective.— The final section of this 3‐part review analyzes published reports involving the acute treatment of migraine with opioids, non‐steroidal anti‐inflammatory drugs (NSAIDs), and steroids in the emergency department (ED), urgent care, and headache clinic settings, as well as post‐discharge medications. In the Conclusion, there is a general discussion of all the therapies presented in the 3 sections. Method.— Using the terms (“migraine” AND “emergency”) AND (“therapy” OR “treatment”), the author searched MEDLINE for reports from ED and urgent care settings that involved all routes of medication delivery. Reports from headache clinic settings were included only if medications were delivered by a parenteral route. Results.— Seventy‐five reports were identified that compared the efficacy and safety of multiple acute migraine medications for rescue. Of the medications reviewed in Part 3, opioids, NSAIDs, and steroids all demonstrated some effectiveness. When used alone, nalbuphine and metamizole were superior to placebo. NSAIDs were inferior to the combination of metoclopramide and diphenhydramine. Meperidine was arguably equivalent when compared with ketorolac and dihydroergotamine (DHE) but was inferior to chlorpromazine and equivalent to the other dopamine antagonists. Steroids afford some protection against headache recurrence after the patient leaves the treatment center. Conclusions.— All 3 opioids most frequently studied – meperidine, tramadol, and nalbuphine – were superior to placebo in relieving migraine pain, although meperidine combined with promethazine was not. Opioid side effects included dizziness, sedation, and nausea. With ketorolac being the most frequently studied drug in the class, NSAIDs were generally well tolerated, and they may provide benefit even when given late in the migraine attack. The rate of headache recurrence within 24‐72 hours after discharge from the ED can be greater than 50%. Corticosteroids can be useful in reducing headache recurrence after discharge. As discussed in Parts 1, 2, and 3, there are effective medications for provider‐administered “rescue” in all the classes discussed. Prochlorperazine and metoclopramide are the most frequently studied of the anti‐migraine medications in the emergent setting, and their effectiveness is superior to placebo. Prochlorperazine is superior or equivalent to all other classes of medications in migraine pain relief. Although there are fewer studies involving sumatriptan and DHE, relatively “migraine‐specific” medications, they appear to be equivalent to the dopamine antagonists for migraine pain relief. Lack of comparisons with placebo and the frequent use of combinations of medications in treatment arms complicate the comparison of single agents to one another. When used alone, prochlorperazine, promethazine, metoclopramide, nalbuphine, and metamizole were superior to placebo. Droperidol and prochlorperazine were superior or equal in efficacy to all other treatments, although they also are more likely to produce side effects that are difficult for a patient to tolerate (especially akathisia). Metoclopramide was equivalent to prochlorperazine, and, when combined with diphenhydramine, was superior in efficacy to triptans and NSAIDs. Meperidine was arguably equivalent when compared with ketorolac and DHE but was inferior to chlorpromazine and equivalent to the other neuroleptics. Sumatriptan was inferior or equivalent to the neuroleptics and equivalent to DHE when only paired comparisons were considered. The overall percentage of patients with pain relief after taking sumatriptan was equivalent to that observed with droperidol or prochlorperazine. (Headache 2012;52:467‐482)     

A Sumatriptan Iontophoretic Transdermal System for the Acute Treatment of Migraine

Objective.— Gastrointestinal symptoms, such as nausea and vomiting, occur almost universally at one time or another in patients during a migraine attack. One third of patients who experience migraine‐related nausea report that this symptom interferes with their ability to take oral medications. The sumatriptan iontophoretic transdermal system (NuPathe Inc., Conshohocken, PA, USA) uses proprietary technology to circumvent the gastrointestinal tract while delivering triptan therapy. This phase III randomized, double‐blind, placebo‐controlled trial evaluated the efficacy and tolerability of this system for the acute treatment of migraine. Methods.— Patients were randomized to treat a single moderate‐to‐severe migraine attack with the sumatriptan iontophoretic transdermal system or placebo. The primary end point was the proportion of patients who were headache pain‐free 2 hours after patch activation. Other end points included the proportions of patients who reported headache pain relief, and freedom from nausea, photophobia, and phonophobia; rescue medication use; and tolerability. Results.— Four hundred sixty‐nine patients were treated. Significantly more patients treated with the sumatriptan iontophoretic transdermal system compared with placebo experienced freedom from headache pain, nausea, photophobia, and phonophobia 2 hours after patch activation, experienced rapid and sustained headache pain relief, and used less rescue medication. Treatment‐emergent adverse events were reported by 50% and 44% of patients treated with the sumatriptan iontophoretic transdermal system and placebo, respectively. Most events were transient mild‐to‐moderate application‐site reactions. Conclusions.— The sumatriptan iontophoretic transdermal system is effective and well tolerated, and may be particularly useful in patients with migraine‐related gastrointestinal symptoms such as nausea.     

Rescue therapy for acute migraine, part 2: neuroleptics, antihistamines, and others

Objectives.— This second portion of a 3‐part series examines the relative effectiveness of headache treatment with neuroleptics, antihistamines, serotonin antagonists, valproate, and other drugs (octreotide, lidocaine, nitrous oxide, propofol, and bupivacaine) in the setting of an emergency department, urgent care center, or headache clinic. Methods.— MEDLINE was searched using the terms “migraine” AND “emergency” AND “therapy” OR “treatment.” Reports were from emergency department and urgent care settings and involved all routes of medication delivery. Reports from headache clinics were only included if medications were delivered by a parenteral route. Results.— Prochlorperazine, promethazine, and metoclopramide, when used alone, were superior to placebo. Droperidol and prochlorperazine were superior or equal in efficacy to all other treatments, although they also have more side effects (especially akathisia). Metoclopramide was equivalent to prochlorperazine and, when combined with diphenhydramine, was superior in efficacy to triptans and non‐steroidal anti‐inflammatory drugs. Meperidine was inferior to chlorpromazine and equivalent to the other neuroleptics. The overall percentage of patients with pain relief after taking droperidol and prochlorperazine was equivalent to sumatriptan. Conclusions.— Prochlorperazine and metoclopramide are the most frequently studied of the anti‐migraine medications in the emergent setting, and the effectiveness of each is superior to placebo. Prochlorperazine is superior or equivalent to all other classes of medications in producing migraine pain relief. Dopamine antagonists, in general, appear to be equivalent for migraine pain relief to the migraine‐“specific” medications sumatriptan and dihydroergotamine, although there are fewer studies involving the last two. Lack of comparisons to placebo and the frequent use of combination medications in treatment arms complicate the comparison of single agents to one other.     

How to Apply the AHS Evidence Assessment of the Acute Treatment of Migraine in Adults to your Patient with Migraine

The “Acute Treatment of Migraine in Adults: The American Headache Society Evidence Assessment of Migraine Pharmacotherapies” provides levels of evidence for medication efficacy for acute treatment of migraine. The goal of this companion paper is to provide guidance on how to choose between evidence‐based treatment options, and, based on the clinical characteristics of the patient and their migraine attacks, to provide guidance on designing an individualized strategy for managing migraine attacks. The acute pharmacological treatments described in the American Headache Society evidence assessment can be divided into those initially taken by the patient during the headache phase of the migraine attack, those taken by the patient later in the attack when initial treatments fail, and those administered intravenously or intramuscularly in urgent care settings. Medications taken initially by patients in the headache phase include nonspecific analgesics such as acetaminophen and nonsteroidal anti‐inflammatory drugs (NSAIDs), triptans, and dihydroergotamine (DHE). A stratified approach to treatment is advised, with the choice of medication based on the patient's treatment needs, taking into consideration the attack severity, presence of associated symptoms such as nausea and vomiting, and the degree of migraine‐related disability. Individuals with migraine may find reassurance in having a “back‐up plan” in the event of an initial acute treatment failure. For those individuals who had a partial response to the initial acute treatment, a second dose might be indicated. When the initial treatment does not provide meaningful and sustained benefits, a treatment from a different medication class is typically chosen. Depending upon the initial treatment used, this might include NSAIDs, triptans, or DHE. Opioids or acetaminophen in combination with codeine or tramadol can be considered as part of the “back‐up plan,” provided they are used infrequently. When all patient administered treatments have failed and moderate to severe migraine symptoms remain, some individuals seek treatment in urgent care settings. The intravenous administration of antiemetics with or without an intravenous or intramuscular NSAID or DHE, or an intramuscular opioid can be considered. Patients with migraine should be encouraged to treat migraine pain early, and avoid overuse of medications.     

Transdermal sumatriptan for acute treatment of migraineurs with baseline nausea

Objective.— To evaluate the efficacy and safety of transdermal sumatriptan in migraine patients who have baseline nausea. Background.— Migraine‐associated nausea and vomiting can limit the effectiveness of acute treatment with oral agents by causing delays, avoidance, or incomplete absorption of medication due to post‐dose vomiting. Methods.— In a multicenter, randomized, double‐blind, placebo‐controlled study in adult (aged 18‐66 years) migraineurs, 530 patients were randomized to receive transdermal sumatriptan or a placebo patch and remained in the study until they had treated a single moderate to severe migraine attack or had gone 2 months without treatment. At baseline (before applying the study patch), patients recorded headache pain intensity and the presence or absence of migraine‐associated symptoms, including nausea. The use of analgesic or anti‐emetic rescue medications within 2 hours of patch activation was prohibited. Post‐hoc analyses were conducted to assess the proportion of patients with nausea at baseline who experienced headache relief and who were free from nausea, photophobia, and phonophobia at 1 and 2 hours post‐activation. Results.— A total of 454 patients were included in the intent‐to‐treat population for efficacy analyses. Baseline demographic and migraine headache characteristics were generally similar between the treatment groups. In the overall study population, transdermal sumatriptan was significantly superior to placebo at 1 hour post‐activation for pain relief (29% vs 19%, respectively; P < .0135) and freedom from nausea (71% vs 58%, respectively; P < .05) and at 2 hours post‐activation for freedom from pain (18% vs 9%, respectively; P < .009), pain relief (53% vs 29%, respectively; P < .0001), freedom from nausea (84% vs 63% respectively; P < .001), freedom from photophobia (51% vs 36%, respectively; P < .0028), freedom from phonophobia (55% vs 39%, respectively; P < .0002); and freedom from migraine (16% vs 8%, respectively; P < .0135). In the post‐hoc analysis, transdermal sumatriptan was markedly superior to placebo for pain relief and freedom from pain, nausea, photo‐, and phonophobia at 1 and 2 hours post‐activation. Conclusions.— Transdermal sumatriptan is superior to oral triptans for migraine patients whose baseline nausea causes them to delay or avoid acute treatment.     

Rescue therapy for acute migraine, part 1: triptans, dihydroergotamine, and magnesium

Objective.— To review and analyze published reports on the acute treatment of migraine headache with triptans, dihydroergotamine (DHE), and magnesium in emergency department, urgent care, and headache clinic settings. Methods.— MEDLINE was searched using the terms “migraine” and “emergency,” and “therapy” or “treatment.” Reports from emergency department and urgent care settings that involved all routes of medication delivery were included. Reports from headache clinic settings were included only if medications were delivered by a parenteral route. Results.— Acute rescue treatment studies involving the triptans were available for injectable and nasal sumatriptan, as well as rizatriptan. Effectiveness varied widely, even when the pain‐free and pain‐relief statistics were evaluated separately. As these medications are known to work best early in the migraine, part of this variability may be attributed to the timing of triptan administration. Multiple studies compared triptans with anti‐emetics, dopamine antagonists, and non‐steroidal anti‐inflammatory drugs. The overall percentage of patients with pain relief after taking sumatriptan was roughly equivalent to that recorded with droperidol and prochlorperazine. Sumatriptan was equivalent to DHE when only paired comparisons were performed. While the data extracted suggest that magnesium may be effective in treating all symptoms in patients experiencing migraine with aura across all migraine patients, its effectiveness seems to be limited to treating only photophobia and phonophobia. Conclusions.— Although there are relatively few studies involving health‐care provider‐administered triptans or DHE for acute rescue, they appear to be equivalent to the dopamine antagonists for migraine pain relief. The relatively rare inclusion of a placebo arm and the frequent use of combination medications in active treatment arms complicate the comparison of single agents with each other.     

Defining Refractory Migraine: Results of the RHSIS Survey of American Headache Society Members

Objectives.— To gauge consensus regarding a proposed definition for refractory migraine proposed by Refractory Headache Special Interest Section, and where its use would be most appropriate. Background.— Headache experts have long recognized that a subgroup of headache sufferers remains refractory to treatment. Although different groups have proposed criteria to define refractory migraine, the definition remains controversial. The Refractory Headache Special Interest Section of the American Headache Society developed a definition through a consensus process, assisted by a literature review and initial membership survey. Design.— A 12‐item questionnaire was distributed at the American Headache Society meeting in 2007 during a platform session and at the Refractory Headache Special Interest Section symposium. The same questionnaire was subsequently sent to all American Headache Society members via e‐mail. A total of 151 responses from AHS members form the basis of this report. The survey instrument was designed using Survey Monkey. Frequencies and percentages of the survey were used to describe survey responses. Results.— American Headache Society members agreed that a definition for refractory migraine is needed (91%) that it should be added to the International Classification of Headache Disorders‐2 (86%), and that refractory forms of non‐migraine headache disorders should be defined (87%). Responders believed a refractory migraine definition would be of greatest value in selecting patients for clinical drug trials. The current refractory migraine definition requires a diagnosis of migraine, interference with function or quality of life despite modification of lifestyle factors, and adequate trials of acute and preventive medicines with established efficacy. The proposed criteria for the refractory migraine definition require failing 2 preventive medications to meet the threshold for failure. Although 42% of respondents agreed with the working definition of refractory migraine, 43% favored increasing the number to 3 (50%) or 4 (26%) preventive treatment failures. When respondents were asked if they felt that the proposed definition was appropriate to select patients for invasive procedures (patent foramen ovale repair or stimulators) only 44% agreed. Conclusions.— There is a consensus for a need for a definition for refractory migraine and that it should be added to the International Classification of Headache Disorder‐2. There was also general agreement by the responders that refractory forms of non‐migraine headache disorders should be defined.     

Long‐Term Use and Safety of Migraine Preventive Medications

Migraine preventive medications are used to reduce the frequency, severity, and disability of migraine attacks. Once migraine preventive therapy is initiated, the question of how long to maintain this therapy arises. This article will explore the literature pertaining to the long‐term use of migraine preventive medications, including length of treatment and safety with long‐term exposure.     

Tolerance to the beneficial effects of prophylactic migraine drugs: a systematic review of causes and mechanisms

Loss of benefit of a previously effective treatment regimen, also known as tolerance, can be an important barrier to the successful preventive treatment of migraine. We undertook a systematic review of the literature to identify the prevalence and possible mechanisms of drug tolerance in migraine prophylaxis. Results demonstrate that the frequency of tolerance to prophylactic migraine treatment is unknown, but available data support an estimate that it occurs in 1-8% of patients receiving prophylaxis. Four broad types of tolerance were identified that are likely to be relevant to migraine prophylaxis. These are pharmacokinetic, pharmacodynamic, behavioral, and cross tolerance. The mechanisms that underlie these types of tolerance determine whether their effects can be overcome or minimized. For example, certain forms of tolerance may be affected by manipulation of environmental cues associated with drug administration, by the order in which drugs are used, and by the concomitant use of other medications. Many medications used for migraine prophylaxis exert their effects through the endogenous opioid system. The implications of this finding are explored, particularly the parallels between medication overuse headache and tolerance to migraine prophylaxis. Given the many ways in which tolerance to migraine medications may develop, in some ways it is not surprising that migraine-preventive drugs stop working; it is more surprising that in many cases they do not.     

Drug and dietary interactions of the new and emerging oral anticoagulants

Oral warfarin is associated with extensive food and drug interactions, and there is a need to consider such interactions with the new oral anticoagulants (OACs) dabigatran etexilate, rivaroxaban and apixaban. A literature survey was conducted using PubMed, EMBASE and recent abstracts from thrombosis meetings to identify publications related to food, drug and dietary supplement interaction studies with dabigatran etexilate, rivaroxaban and apixaban. Clinical experience regarding food interactions is currently limited. Regarding drug–drug interactions, dabigatran requires caution when used in combination with strong inhibitors or inducers of P‐glycoprotein, such as amiodarone or rifampicin. Rivaroxaban (and possibly apixaban) is contraindicated in combination with drugs that strongly inhibit both cytochrome P450 3A4 and P‐glycoprotein, such as azole antimycotics, and caution is required when used in combination with strong inhibitors of only one of these pathways. Important drug interactions of the new OACs that can lead to adverse clinical reactions may also occur with non‐steroidal anti‐inflammatory drugs and antiplatelet drugs, such as aspirin and clopidogrel. Over‐the‐counter (OTC) medications and food supplements (e.g. St. John’s Wort) may also interact with the new OACs. Given the common long‐term use of drugs for some chronic disorders, the frequent use of OTC medications and the need for multiple treatments in special populations, such as the elderly people, it is essential that the issue of drug interactions is properly evaluated. New OACs offer significant potential advantages to the field of venous thromboprophylaxis, but we should not fail to appreciate their lack of extensive clinical experience.     

Twelve-month tolerability and efficacy study of NP101, the sumatriptan iontophoretic transdermal system

Objective.— To assess the long‐term tolerability and efficacy of NP101, a novel transdermal sumatriptan patch being developed for the acute treatment of migraine. Background.— Nausea (with or without vomiting) and gastroparesis have been characterized as being among the most problematic challenges affecting migraine care today. Migraine‐associated nausea can cause patients to delay or avoid taking oral medication with a resultant loss or reduction of therapeutic efficacy. Migraine‐associated gastroparesis can impair absorption and reduce bioavailability of oral migraine medications and thereby reduce and delay therapeutic efficacy. The non‐oral triptan formulations that have been used to overcome these challenges are associated with other shortcomings that can limit their use. Designed to overcome these shortcomings and treatment limitations imposed by gastrointestinal signs and symptoms, the NP101 patch avoids the need for oral administration, does not depend upon gastrointestinal absorption, and provides more consistent, predictable plasma concentrations than oral and intranasal formulations of sumatriptan and a lower maximum plasma concentration than sumatriptan injection. Methods.— Patients diagnosed with migraine who had participated in a randomized, double‐blind, Phase III study of the NP101 patch were given the option to use NP101 to treat migraine episodes with moderate or severe headache pain for up to 12 months in this open‐label trial. Results.— One hundred eighty‐three patients applied 2089 study patches. The most common adverse events involved the patch application site (45% of patients). The only non‐application‐site adverse events reported in >2% of patients were nausea (n = 6, 3.3%), upper respiratory tract infection (n = 6, 3.3%), and nasopharyngitis (n = 4, 2.2%). The incidence of triptan‐associated adverse events was 1.6%. Across all visits for investigator assessments, the majority of patients (ranging from 74.7% at Month 1 to 92.2% at Month 9) were scored as having no erythema at patch application sites. For patient assessments, the percentage of patch placement sites scored as having no or minimal redness was 38.2% at the time of patch removal and 65.4% 24 hours after patch activation. Two hours after patch activation across all patch treatments over the 12‐month study, 23.8% of initial acute migraine episodes were scored as being free from headache pain, 58.2% as having headache pain relief,78.9% as nausea free, 60.1% as phonophobia free, 53.4% as photophobia free, and 20.7% as migraine free. No evidence of waning tolerability or efficacy was observed over the 12‐month study period. Conclusion.— NP101, a transdermal sumatriptan formulation in development for the acute treatment of migraine, demonstrated tolerability and efficacy with successive uses over 12 months in this clinical trial.     

Migraine headache. Its diagnosis and treatment

Many theories exist on the pathogenesis of migraine. However, the clinical picture of migraine is agreed on universally as a familial disorder characterized by recurrent attacks of headache that are variable in intensity, frequency, and duration. The attacks are usually unilateral and often associated with anorexia, nausea, and vomiting. Migraine therapy is complex and difficult, focusing on abortive and prophylactic regimens. General therapeutic measures, including diet and establishing schedules for meals and sleeping, may benefit many migraineurs. A variety of medications, including ergotamine, propranolol, the calcium channel blockers, antidepressants, and nonsteroidal anti-inflammatory drugs (NSAIDs) have been beneficial in the prophylactic treatment of migraine. Ergotamine is the drug of choice in the abortive treatment, although other agents, such as the NSAIDs, have been used successfully. Inpatient therapy in a specialized unit for headache patients may be indicated for the recidivist patient, the patient habituated to analgesics or ergotamine, or the patient with the mixed headache syndrome, i.e., migraine occurring with coexistent muscle contraction headaches.     

Topiramate in Migraine Prevention

The efficacy of topiramate in migraine prevention (prophylaxis) was established in two multicenter, randomized, double-blind, placebo-controlled, pivotal trials. Topiramate has received regulatory approval for use in adults for migraine prophylaxis (prevention) in the US and numerous other countries, including France, Ireland, Switzerland, Brazil, Taiwan, Spain, and Australia. Treatment with 100 or 200 mg per day of topiramate was associated with significant reductions in the frequency of migraine headaches, number of migraine days, and use of acute medications. No increase in efficacy was observed between 100 and 200 mg per day of topiramate. Based on efficacy and tolerability, 100 mg per day of topiramate should be the initial target dose for most patients. The most common adverse events were paresthesia, fatigue, decreased appetite, nausea, diarrhea, weight decrease, and taste perversion. Topiramate is a first-line migraine preventive drug and should especially be considered as a preferred treatment for all patients who are concerned about gaining weight, who are currently overweight, or who have coexisting epilepsy.     

Amlodipine for migraine prophylaxis

Migraine is among the most common neurologic disorders encountered in clinical practice. In the general US population, the annual incidence has been calculated to be approximately 250 per 100,000 with a point prevalence of 10%. Females are affected more than males. A variety of prophylactic and abortive medications are being used for treatment and several are being studied in clinical trials. Calcium-channel blockers are frequently used prophylactic medications. We report two patients with migraine successfully treated with amlodipine (Norvasc, Pfizer, Inc), a slow calcium-channel blocker. To our knowledge, these are the first reported cases of amlodipine used in migraine prophylaxis.